The ultimate goal of this project is the identification of a gene or genes whose polymorphisms within the American population determine the risk of developing colon polyps and cancers among average adults. This will be accomplished by identifying and collecting DNA from a cohort of 300 pairs of siblings in which the two members of each sibship have each developed colon neoplasia by age 65 or younger. Using the powerful genetic algorithm of affected sibling pair linkage analysis, we will use this cohort of concordantly affected sibling pairs to examine the entire human genome to identify loci linked to colon neoplasia susceptibility in adults. Colon cancer is the second most common cause of cancer death among adult Americans. These cancers develop from premalignant precursor lesions known as adenomatous colon polyps. Multiple epidemiological studies have demonstrated that once one member of a family has developed an adenomatous colon polyp, his or her other siblings are at markedly elevated risk for developing both colon adenomas and colon cancers. These studies are consistent with 20 percent of all Americans carrying a dominant "colon neoplasia susceptibility" gene with 40 percent by age 60. An apparently rare, but illustrative, example of one such colon neoplasia susceptibility variant is the finding that 6 percent of Ashkenazi Jews carry the I1307K APC variant whose DNA sequence is predisposed to in adult life undergo second hit somatic mutations that inactivate APC tumor suppressor activity. This I1307K APC variant is not present outside the Ashkenazi population. It is thus a pressing question to answer whether other APC gene variants exist and are the missing colon neoplasia susceptibility genes in the broader population. Moreover, variant murine alleles of COX2, sPLA2, and DNMT genes can suppress or promote neoplasias in mice that are genetically predisposed to intestinal tumor development. It is thus a pressing question to answer whether human variants of these genes are present as major colon neoplasia susceptibility genes in man. The specific aims of this proposal are accordingly to identify and to obtain DNA from 300 affected sibling pairs in which both sibs are concordant for a history of colon neoplasia; to exclude from this cohort any sibships with known familial colon cancer syndromes (FAP, HNPCC, or APC-I1307K carriage); to test 4 candidate susceptibility genes (APC, COX2, sPLA2, DNMT) for linkage to colon neoplasia development among these sibships via an affected sibling pair linkage analysis; and to identify novel colon neoplasia susceptibility loci by similarly testing for linkage each of 350 microsatellite markers that span regions encompassing the entire human genome.